Novel processes for producing sovaprevir

ABSTRACT

The disclosure includes novel processes for producing Sovaprevir comprising adding 
     
       
         
         
             
             
         
       
     
     compound E to F-1 to provide Sovaprevir. The disclosure further includes intermediates useful for producing Sovaprevir. The disclosure also include a novel crystalline form of Sovaprevir, Form F, and a method for preparing spray-dried amorphous Sovaprevir from crystalline Form F.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application No.61/784,182, filed Mar. 14, 2013, which is hereby incorporated byreference in its entirety.

BACKGROUND

Sovaprevir is a hepatitis C virus NS3 protease inhibitor, effective fortreating HCV infection in humans.

Sovaprevir can be prepared by the method presented in U.S. Pat. No.7,906,619, Example 1.

SUMMARY

The disclosure provides methods of preparing Sovaprevir. These methodsare designated Methods 1 and 2 in the EXAMPLES section of theapplication. A number of the steps in the methods are unique as are theoverall methods for preparing Sovaprevir. The disclosure provides thesteps occurring after the synthesis of Compound 13 in synthetic Method 1to form Sovaprevir. The disclosure also provides the addition ofCompound F-1 to Compound E to form Sovaprevir. The formation of theproduct in Scheme IX, Method 2, (Compound IX) is provided, as is theformation of Sovaprevir from the steps occurring after the formation ofthe Scheme IX product.

The disclosure also provides intermediates useful for preparingSovaprevir and close analogues of Sovaprevir. Particularly thedisclosure provides, as useful intermediates, at least Compounds 13, 14,15, C, C-1, and D in Method 1, the compounds of Schemes IX, X, and XI,F, F-1 (the first compound of Scheme XIII in Method 2), and F-2.

The disclosure provides a crystalline polymorph, Form F.

The disclosure further provides a bioavailable amorphous form ofSovaprevir and a method for making the amorphous form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Amino acids residues P1′, P1, P2, P2 Top, P3, and P4 as presentin sovaprevir.

FIG. 2 is a graph of intensity (counts per second, CPS) versusscattering angle (degrees 20) showing the results of X-ray powderdiffraction analysis of the Form F presented in Example 9.

FIG. 3 is a graph of heat flow (Watts per gram, W/g) versus temperature(° C.) showing the results of differential scanning calorimetry analysisof the Form F polymorph, sample size 0.990 mg. Additional experimentaldetails for the DSC analysis are provided in Example 9.

FIG. 4. is a graph of weight (percent) versus temperature (° C.) showingthe results of thermogravimetric analysis of the Form F polymorph. Theanalysis was performed on a 3.4990 mg sample. Analysis was performedusing a TA Instruments 2950 thermogrametric analyzer. Data werecollected by heating under nitrogen at a rate of 10° C./min to a maximumtemperature of 350° C.

DETAILED DESCRIPTION

Starting materials for sovaprevir production are prepared by methodsknown in the art. For example Compound A (tert-butyl((1R)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate)is prepared by the method discussed in WO 2006/122188, page 34, SchemeIII and pages 77-78. This procedure is illustrated in Scheme I.

Compound B ((S)-4-(tert-butoxy)-2-(tert-butyl)-4-oxobutanoic acid) isprepared by the method discussed in Evans et. al. J. Org. Chem. 1999,64, 6411-6417. The synthesis of Compound B is shown in Scheme II.

Compound D (4-chloro-7-methoxy-2-phenylquinoline) is prepared by themethod reported in WO 2000/009543, page 51. This method is illustratedin Scheme III

Sovaprevir is a peptidomimetic compound comprised of amino acid likeresidues P1′, P1, P2, P2-Top, P3, and P4. The presence of these residuesin Sovaprevir is shown in FIG. 1. The sequence of steps utilized toattach the amino acid residues can vary. Examples 1 through 5 providetwo methods by which amino acid residues P1′, P1, P2, P2-Top, P3, and P4can be attached to form sovaprevir. However, other sequences forattaching the amino acid residues to form sovaprevir are possible andwill be readily apparent to those of skill in the art.

The disclosure provides a method of preparing Sovaprevir comprisingadding Compound F-1 to Compound E to provide Sovaprevir as follows:

This method may additionally comprise adding4-chloro-7-methoxy-2-phenylquinoline to Compound C-1, to provideCompound F-1 as follows:

prior to adding Compound F-1 to Compound E.

The disclosure also provides a method of preparing a compound of formula(C) comprising at least Step 3 of the following 3 step process, wherein

Step 1 comprises deprotecting Compound 13 with acid to provide Compound14

Step 2 comprises coupling R₁H in base to Compound 14 to provide Compound15;

andStep 3 comprises demethylating Compound 15 with base to provide CompoundC

where R₁ is a Nitrogen bound 4- to 7-membered heterocycloalkyl ringcontaining 0 to 2 additional heteroatoms independently chosen from N, O,and S which ring is optionally fused to a 5- or 6-membered heterocyclicring, containing 1 or 2 heteroatoms independently chosen from N, O, andS, or 5- or 6-membered carbocyclic ring to form a bicyclic ring system,each of which 5- to 7-membered heterocycloalkyl ring or bicyclic ringsystem is optionally substituted with 0 to 2 substituents independentlychosen from fluoro, amino, hydroxyl, methyl, and trifluoromethyl. Incertain embodiments R₁ is a 1-piperidinyl, 1-piperazinyl, or1-pyrrolidinyl group, each of which is unsubstituted or substituted with1 or 2 halogen substituents. In certain embodiments Step 2 includescoupling piperidine in base. In this caseStep 2 comprises coupling piperidin in base to Compound 14 to provideCompound 17;

andStep 3 comprises demethylating Compound 17 with base to provide CompoundC-1

In certain embodiments R₁ is a 3,3-difluoropiperidin-1-yl group or R₁ isa 1-piperidinyl group.

The disclosure includes the above method for preparing Compound C,comprising Steps 2 and 3 of the method, where R₁ may carry any of thedefinitions set forth above for this variable.

The disclosure includes the above method for preparing Compound C,comprising Steps 1, 2, and 3 of the method, where R₁ may carry any ofthe definitions set forth above for this variable.

The disclosure includes a method of preparing Compound F-2, comprisingadding 4-chloro-7-methoxy-2-phenylquinoline to Compound C, to provideCompound F-2 as follows:

Where R₁ may carry any of the values set forth for this variable in themethod for producing compound C, above. In certain embodiments of themethod for producing Compound F-2, R₁ is a 1-piperidinyl, 1-piperazinyl,or 1-pyrrolidinyl group, each of which is unsubstituted or substitutedwith 1 or 2 halogen substituents, or R₁ is a 1-piperidinyl group.

The disclosure includes an intermediate useful in the processesdescribed in this disclosure, of the Formula C-2

R₁ in Formula C-2 may carry any of the definitions set forth above. Incertain embodiments R₁ is C₁-C₆alkyl or hydroxyl, or R₁ is a1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl group, each of which isunsubstituted or substituted with 1 or 2 halogen substituents; and R₂ ishydrogen or C₁-C₆alkyl, or R₂ is methyl.

The disclosure includes intermediates of Formula C or C-2, in which R₁is t-butoxy, hydroxyl, or 1-piperidine, and R₂ is methyl.

In certain embodiment the intermediate is a compound of Formula C-1.

The disclosure also includes intermediate of Formula F useful forpreparing Sovaprevir.

R₁ and R₂ in Formula F, may carry any of the definitions set forth abovefor these variables. In certain embodiments R₁ is a 1-piperidinyl,1-piperazinyl, or 1-pyrrolidinyl group, each of which is unsubstitutedor substituted with 1 or 2 halogen substituents; and R₂ is hydrogen ormethyl.

In certain embodiments the intermediate of Formula F is a compound ofFormula F-1.

In other embodiments the disclosure includes compounds having theformula of any of Compounds IX, X, or XI:

The disclosure includes the method for making Sovaprevir shown above,comprising adding Compound F-1 to Compound E to provide Sovaprevir, and,additionally comprising the step of hydrolyzing the ester in compound XIwith base to form F-1 as follows:

This step is performed prior to adding Compound F-1 to Compound E toprovide Sovaprevir.

The disclosure also provides a method of preparing a pure amorphous formof Sovaprevir, comprising: crystallizing Sovaprevir in isopropyl alcoholto form Sovaprevir crystalline Form F in greater than 98% purity;dissolving the Sovaprevir crystalline Form F in 6-12 volumes of asolvent such as acetone; adding 6-13 volumes water relative to volumeacetone; and precipitating amorphous Sovaprevir.

The disclosure provides a method of preparing a pure amorphous form ofSovaprevir, comprising crystallizing Sovaprevir in isopropyl alcohol toform Sovaprevir crystalline Form F in greater than 98% purity;dissolving Form F in a solvent such as acetone to form dissolvedSovaprevir; and spray drying the dissolved Sovaprevir to form anamorphous Sovaprevir.

The disclosure provides a crystalline Sovaprevir form, comprisingpolymorph F.

The crystalline Sovaprevir of Form F has the characteristic 2θ values ofFIG. 2.

The crystalline Sovaprevier form of Form F is characterized by an X-raypowder diffraction pattern obtained from a Cu Kα_source which comprisespeaks at 2θ values of 4.2, 8.8, 13.0, and 19.9+/−0.2; or 9.7, 13.5,14.9, 19.0, 19.6, 20.9, and 23.0+/−0.2; or 10.4, 17.1, 25.5, 26.1, 26.6,and 27.2+/−0.2.

The crystalline Sovaprevir of Form F has a melting point of 216° C. to226° C.

The crystalline Sovaprevir of Form F has a primary endothem at 225° C.as determined by DSC.

EXAMPLES Abbreviations

The following abbreviations may be useful when reviewing the schemes andexamples of this disclosure.

-   -   DCM Dichloromethane    -   DIEA/DIPEA N,N-diisopropylethylamine    -   DMF Dimethyl formamide    -   DMSO Dimethyl Sulfoxide    -   DSC Differential Scanning calorimetry    -   EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   HATU        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate)    -   HOBt Hydroxybenzotriazole    -   IPA Isopropyl Alcohol    -   KO^(t)Bu Potassium Butoxide    -   MeOH Methanol    -   MTBE Methyl tert-Butyl Ether    -   TBTU o-(Benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium        tetrafluoroborate    -   THF Tetrahydrofuran    -   TFA Trifluoroacetic Acid

Example 1 Synthesis of(2S,4R)-1-((S)-2-(tert-butyl)-4-oxo-4-(piperidin-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (Compound C-1)

The synthesis of Compound C-1 is illustrated by Scheme IV. Examples 1-4provide a complete method for synthesizing sovaprevir. This method isdesignated as Method 1.

HATU (1.3 equivalent) was added to a mixture of hydroxyproline, 16 (1.5equivalent), diisopropyl ethyl amine (5 equivalent) and acid B (1equivalent) in dimethylformamide at a temperature between 5-25° C. Thereaction was stirred for 15 h at room temperature, diluted with waterand extracted with methyl t-butylether (MTBE). The organic layer waswashed with 1M citric acid and brine. The organic layer was concentratedand residue crystallized from a mixture of MTBE/heptane to give compound13.

Compound 13 was treated with trifluoroacetic acid in dichloromethane(2.3:5 v/v) to remove the t-butyl group. All the volatiles were removedand the material (compound 14) taken forward without purification to thenext step.

Piperidine (1.2 equivalents) was added at ˜5° C. to a solution ofCompound 14, diisopropyl ethylamine (8.5 equivalents), EDC.HCl (1.3equivalents), HOBt (0.14 equivalent) in dichloromethane. The reactionwas stirred till completion at room temperature, diluted withdichloromethane, and washed with 1M citric acid followed by brine togive compound 17. Other peptide coupling agents may be used in place ofEDC.HCl. These include N,N″-Dicyclohexylcarbodiimide (DCC), triazolecoupling agents such asN,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate(TBTU), [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU), andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), or pyridium coupling agents such as 2-Chloro-1-methylpyridiniumiodide (Mukaiyama's reagent) and other peptide coupling agents wellknown in the art.

Compound 17 (1 equivalent) was dissolved in a mixture of THF/MeOH/water(4/0.17/1 v/v) and lithium hydroxide (1.2 equivalents) was added. Thereaction was stirred till hydrolysis was complete (by HPLC). Thereaction was evaporated to dryness, diluted with water and extractedwith MTBE. The aqueous layer was acidified with HCl and extracted withdichloromethane. The organic layer was dried and concentrated and theresidue crystallized from MTBE to give compound C-1.

Example 2 Synthesis of(1R)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamidehydrochloride (Compound E)

Scheme V illustrates the synthesis of Compound E.

To a solution of compound A in 1,4-dioxane was added 4M HCl in dioxaneand stirred for 3 h at room temperature. The reaction mixture wasevaporated to dryness to give Compound E which was used for the nextstep without further purification.

Example 3 Synthesis of(2S,4R)-1-(S)-2-(tert-butyl)-4-oxo-4-(piperidin-1-yl)butanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylicacid (Compound F-1)

Scheme VI illustrates the preparation of Compound F-1.

Potassium t-butoxide (2.5 equivalent) was added in portion to a solutionof compound C-1 (1 equivalent) and the chloroquinoline D (1.0equivalent) in dimethylsulfoxide and stirred for 24 h at roomtemperature. The reaction mixture was diluted with dichloromethane andwashed with 1M citric acid and concentrated. The residue was trituratedwith MTBE and the solid isolated by filtration. The solid wascrystallized from isopropyl alcohol, cooled to ˜3° C. and filtered togive Compound F-1.

Example 4 Preparation of Sovaprevir

To a solution of Compound F-1 (1 equivalent), compound E (1 equivalent)and TBTU (1.3 equivalent) in dimethylformamide was addeddiisopropylethyl amine (5 equivalent) and stirred for 15 h at roomtemperature. The reaction mixture was diluted with ethylacetate, washedwith 1M citric acid, 1M LiOH followed by 1M citric acid and brine. Thesolution is treated with charcoal and concentrated. The residue wastriturated in hot heptane cooled and filtered to give Sovaprevir Crude.Sovaprevir Crude is crystallized from isopropyl alcohol to obtainpurified Sovaprevir. Crystallizations from isopropyl alcohol (IPA) willgenerally produce a crystalline form that is soluble in acetone andtypically crystalline Form F is produced.

Sovaprevir is amorphous in nature and is produced by precipitating asolution of Sovaprevir Purified in acetone into water. Sovaprevirpurified is dissolved in 6-12 volumes of acetone and this solution isadded to water (6.7 to 12 volumes in relation to acetone used) withvigorous stirring. The precipitated solid is filtered and dried toobtain sovaprevir.

Sovaprevir Purified is dissolved in acetone and spray dried to obtainamorphous Sovaprevir.

Example 5 Preparation of Sovaprevir (Method 2)

Schemes VIII through XIII illustrated the preparation of Sovaprevir byMethod B.

Lactone 18 is reacted in the presence of an acid catalyst such asamberlyst for a suitable time and temperature to obtain cis-hydroxy proline methyl ester, 19, in high yield.

Cis-hydroxyproline methylester, 19, is reacted with compound B inpresence of HATU and diisopropylethylamine in DMF to give compound IX asdescribed in example 1.

Compound IX is treated with an acid such as trifluoroacetic acid in asolvent such as dichloromethane to give the acid, compound 20 which isthen reacted with piperidine to give compound X as described in example1.

A solution of compound X is then reacted with Bromobenzene sulfonylchloride (21) in presence of triethylamine and catalyticdimethylaminopyridine in solvent such as dichloromethane to obtain thebrosylate (Compound 22) (methanesulfonyl chloride can also be used tomake the mesylate), which can be used for the next step. The brosylateis then reacted with compound 12 in a solvent such as dimethylformamidein presence of a base such as potassium carbonate or potassium hydroxideor bases of the like to obtain compound XI.

The ester group of compound XI is hydrolyzed to the carboxylic acidusing a base such as lithium hydroxide in a solvent such astetrahydrofuran and water to obtain compound F-1.

Compound F-1 is then treated with compound E as described in example 4.

Example 6 Crystallization of Polymorph F

Form F is crystallized from isopropanol. Form F was characterized bypowder X-ray diffraction (pXRD), differential scanning calorimetry(DSC), thermogravimetric analysis (TG), and hot stage microscopy. Thecharacterization results are presented in FIGS. 2-5.

XRPD patterns were collected using an Inel XRG-3000 diffractometerequipped with a curved position sensitive detector with a 20 range of120°. An incident beam of Cu Kα radiation (40 kV, 30 mA) was used tocollect data in real time at a resolution of 0.03° 2θ. Prior to theanalysis, a silicon standard (NIST SRM 640c) was analyzed to verify theSi 111 peak position. Samples were prepared for analysis by packing theminto thin-walled glass capillaries. Each capillary was mounted onto agoniometer head and rotated during data acquisition. The monochromatorslit was set at 5 mm by 160 μm, and the samples were analyzed for 5minutes. Characteristic peaks are observed at the following 2θ values:4.2, 8.8, 9.7, 10.4, 13.0, 13.5, 14.9, 17.1, 19.0, 19.6, 19.9, 20.9,23.0, 25.5, 26.1, 26.6, and 27.2+/−0.2.

Differential scanning calorimetry (DSC) was performed using a TAInstruments differential scanning calorimeter Q2000. The sample wasplaced into an aluminum DSC pan, and the weight accurately recorded. Thepan was covered with a lid and then crimped. The sample cell wasequilibrated at −50° C. (or 25° C., depending on the sample) and heatedunder a nitrogen purge at a rate of 10° C./min, up to a finaltemperature of 250° C. Indium metal was used as the calibrationstandard. Reported temperatures are at the transition maxima.

Hot stage microscopy was performed using a Linkam hot stage (model FTIR600) mounted on a Leica DM LP microscope equipped with a SPOT Insight™color digital camera. Temperature calibrations were performed using USPmelting point standards. Samples were placed on a cover glass, and asecond cover glass was placed on top of the sample. As the stage washeated, each sample was visually observed using a 20×0.40 N.A. longworking distance objective with crossed polarizers and a first order redcompensator. Images were captured using SPOT software (v. 4.5.9).

Termogravimetric analyses (TGA) were performed using a TA Instruments2950 termogravimetric analyzer. Each sample was placed in an aluminumsample pan and inserted into the TGA furnace. The furnace was heatedunder nitrogen at a rate of 10° C./min, up to a final temperature of350° C. Nickely and ALUMEL were used as the calibration standards.

Example 7 Characterization Data for Polymorph Form F

Sample Source Technique Analysis/Result lot 146-181-2 XRPD Form F LIMS188807, DSC^(a) very minor broad endo 158, endo 225 (57 J/g)crystallized TG^(b) 1.59 @ 25-205° C. from dry IPA 1.34 @ 125-205° C.^(a)endo = endotherm, temperatures (° C.) reported are transitionmaxima. Temperatures are rounded to the nearest degree. ^(b)weight loss(%) at a certain temperature; weight changes (%) are rounded to 2decimal places; temperatures are rounded to the nearest degree.

What is claimed is:
 1. A method of preparing sovaprevir comprisingadding Compound F-1 to Compound E to provide Sovaprevir as follows:


2. The method of claim 1, additionally comprising adding4-chloro-7-methoxy-2-phenylquinoline (Compound D) to Compound C-1, toprovide Compound F-1 as follows:

prior to adding Compound F-1 to Compound E.
 3. A method of preparing acompound of formula (C) comprising at least Step 3 of the following 3step process, wherein Step 1 comprises deprotecting Compound 13 withacid to provide Compound 14

Step 2 comprises coupling R₁H in base to Compound 14 to provide Compound15;

and Step 3 comprises demethylating Compound 15 with base to provideCompound C

where, R₁ is a 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl group,each of which is unsubstituted or substituted with 1 or 2 halogensubstituents.
 4. The method of claim 3, wherein R₁ is a 1-piperidinylgroup.
 5. The method of claim 3, comprising Steps 2 and
 3. 6. The methodof claim 3 comprising Steps 1, 2, and
 3. 7. A method of preparingCompound F-2, comprising adding 4-chloro-7-methoxy-2-phenylquinoline(Compound D) to Compound C, to provide Compound F-2 as follows:

where, R₁ is a 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl group,each of which is unsubstituted or substituted with 1 or 2 halogensubstituents.
 8. The method of claim 7 wherein R₁ is a 1-piperidinylgroup.
 9. The method of claim 7, additionally comprising the followingsynthetic step, in which R₁ is a 1-piperidinyl group


10. The method of claim 9, additionally comprising on or more of Steps1, 2, and 3, where Step 1 comprises deprotecting Compound 13 with acidto provide Compound 14

Step 2 comprises coupling R₁H in base to Compound 14 to provide Compound15;

and Step 3 comprises demethylating Compound 15 with base to provideCompound C

where, R₁ is a 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl group,each of which is unsubstituted or substituted with 1 or 2 halogensubstituents.
 11. A compound having the formula:

where R₁ is C₁-C₆alkyl or hydroxyl, or R₁ is a 1-piperidinyl,1-piperazinyl, or 1-pyrrolidinyl group, each of which is unsubstitutedor substituted with 1 or 2 halogen substituents; and R₂ is hydrogen ormethyl.
 12. A compound of claim 11 in which R₁ is t-butoxy, hydroxyl, or1-piperidine, and R₂ is methyl.
 13. A compound of claim 11 of theformula


14. A compound, having the Formula F

where, R₁ is a 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl group,each of which is unsubstituted or substituted with 1 or 2 halogensubstituents; R₂ is hydrogen or methyl.
 15. A compound of claim 14 ofthe formula


16. A compound of claim 11, having the formula of Compound IX


17. A compound of claim 11, having the formula of Compound X


18. A compound of claim 14, having the formula of Compound XI


19. The process of claim 1, additionally comprising the step ofDemethylating Compound XI with base to form F-1 as follows:

prior to adding Compound F-1 to Compound E to provide Sovaprevir.
 20. Amethod of preparing a pure amorphous form of Sovaprevir, comprisingcrystallizing Sovaprevir in isopropyl alcohol to form Sovaprevircrystalline Form F; dissolving the Sovaprevir crystalline Form F in 6-12volumes acetone; adding 6-13 volumes water relative to volume acetone;and precipitating amorphous Sovaprevir of greater than 98% purity.
 21. Amethod of preparing a pure amorphous form of Sovaprevir, comprisingcrystallizing Sovaprevir in isopropyl alcohol to form Sovaprevircrystalline Form F; dissolving Form F in an acetone to form dissolvedSovaprevir; and spray drying the dissolved Sovaprevir to form anamorphous Sovaprevir of greater than 98% purity.
 22. A crystallineSovaprevir form, comprising polymorph Form F.
 23. The crystallineSovaprevir form of claim 22, having the characteristic 20 values of FIG.2.
 24. The crystalline Sovaprevir form of claim 22, wherein the form ischaracterized by an X-ray powder diffraction pattern obtained from a CuKα_source which comprises peaks at 2θ values of 4.2, 8.8, 13.0, and19.9+/−0.2; or 9.7, 13.5, 14.9, 19.0, 19.6, 20.9, and 23.0+/−0.2; or10.4, 17.1, 25.5, 26.1, 26.6, and 27.2+/−0.2.
 25. The crystallineSovaprevir form of claim 22, wherein polymorph F has a melting point of216° C. to 226° C.
 26. The crystalline Sovaprevir form of claim 22,wherein polymorph F has a primary endothem at 225° C. as determined byDSC.